Believing in Girls with Rett Syndrome

When we first got a diagnosis of Rett Syndrome for Becca we did a lot of Internet searches trying to figure out what we were up against. Paula found a blog called Spirit Dances about a woman with Rett Syndrome named Karly. The blog is authored by Karly as her mother held her hand and helped her type on a keyboard. The posts are complete sentences, complete paragraphs, with a very large and diverse vocabulary.

When I saw the blog I discounted it right away. I'd read about how debilitating Rett Syndrome is, and there was no way this disabled person was writing all that. Maybe she was picking the first letter and her and her mom was filling in the rest -- maybe not even intentionally or anything, but there's lots of research examples of facilitators who in trying to help end up saying things from their own head rather than the individual's. I didn't say any of this in a comment on the blog or anything, I kept it to myself, but I definitely thought it.

I didn't know Karly (she has since passed away) so I'm really in no place to make a judgment call either way, but I've since learned why my attitude is wrong-headed -- mostly by being on the receiving end of some healthy skepticism about Becca's abilities.

Becca is reading words. She only knows 14 letters, but that's enough that she's independently read the words "bat", "bag", "fat", "leg" and "hen". Last week we were trying to come up with Christmas words for all of the letters she knows, and she thought all on her own of "elf" for "e". The next day she asked me how to spell "lion". She out of nowhere last month told us that she hates her car seat, and she told me a few weeks ago that I make her shower water too hot, then helped me find a better temperature. She can count to five and she has just started saying her own prayers at night when she goes to bed.

Hunting for a Christmas tree we all could agree on

If you've seen Becca in real life then those events will probably sound next to impossible. Becca can't talk or sit up or walk, she shakes constantly, she struggles to move her arms intentionally anywhere other than to her mouth and struggles to keep eye contact focused on much of anything. Most people would look at someone in her condition and declare those skills as far out of reach. And if we told you how we know she can do all of those things (because she told us she can) then you'd probably put us squarely in the same bucket I put Karly and her parents in before. I can't really judge you for thinking that way since I sometimes still do myself, but I can try to help you see why you (and I) should rethink assumptions.

I'm going to introduce two probably-new-to-you concepts. The first is called "the least dangerous assumption" and the second is called "presumed competence". They both have to do with the benefit of the doubt, and hopefully will help you see why it's so important for individuals with disabilities.

The least dangerous assumption is a perspective re-think. It's essentially the request to take your assumptions about a person's capabilities and think beyond to the end result of those assumptions. Let's say for example that twenty years from now someone comes up with a drug that completely cures all symptoms of Rett Syndrome. Which would be worse, hearing Becca say "I laid on the floor for twenty years watching baby cartoons. I tried to learn to read but nobody would hold the books still enough" or hearing her say "I know you tried to help me, and I did get a little out of it, but most of the time it was too hard to focus and I didn't learn much"? Henry Frost is a young man with autism who fought this battle, using typing to convince the school that he was capable of learning. The least dangerous assumption is the assumption about an individual's abilities that will cause the least amount of damage if in the end you find out you were wrong.

Presumed competence is related. It's the idea that an individual shouldn't need to earn the right to be taught, respected or spoken to. You should assume that an individual understands what you're teaching them or saying to them or about them, whether they can respond or not. Don't skip explaining things to Becca just because she looks like she's not listening. Don't skip her in activity time with the kids because she's disabled. When Becca responds with what seems like only half or a quarter of what you were told is her typical response, you should take it and believe that it was intentional. Take it the rest of the way. Call it a victory, rather than thinking "that could have been an accident". Presume competence. Don't ask her to prove to you that she has a brain in her head, that's not how you treat "normal" people. If a "normal" kid says "appow" instead of "apple" you don't say "well *that* kid can't talk." I won't lie to you, presuming competence takes a lot more work than you probably think. It involves getting over your own insecurities in addition to the child's, and re-assessing yourself again and again.

Honestly presuming competence has made all the difference in the world with Becca. Once we started introducing concepts and ideas to Becca that were beyond where everyone (including us) assumed she was, she took off. Her yes/no eye gaze didn't get really solid until she started picking from six choices of places to go (backyard, front yard, downstairs, etc.) -- and I'm betting that at least the first few times she didn't completely understand what she was picking. But we took it and ran with it and then went a few steps farther. We didn't know for sure if she'd keep up but she has, again and again. I love the phrase I found a few weeks ago, "we teach intentionality by assuming intentionality." Just as often we we find we're not teaching intentionality so much as finally trusting her enough that she feels she can rely on us for communication. Whenever we feel like she's getting stuck it's usually not because of her understanding, it's because we got sucked back into "you need to prove you know this before we move on" again, and once we fix our side she picks right back up. Will that last forever? We have no idea. But we've heard too many horror stories of girls with Rett in high school who are still working on identifying colors, and we just have to think there's something more stimulating for them than that.

Check me out, I can rock the wink like no other.

Becca's mutation (K135E) is not a common Rett mutation, so I don't know that we can really speak for a majority of girls with Rett Syndrome, but from those we've seen Becca is not on the "light" end of the Rett spectrum, and she is still so very much "in there". We have to believe that most girls with Rett are as much "in there" as Becca. I still wonder about Karly's typing skills (my bad, I know. Why do I worry so much about being "taken in" by an online exaggeration?), but I now believe she was capable of writing a blog, that she could read and understand and benefited from her method of communication. I think it's crucial that we surround our girls with people who believe in them, because I've seen how much of a difference it can make.

If you don't believe Becca can do the things we claim she can do, we understand exactly where you're coming from but please give our daughter the benefit of the doubt. If you want a girl with Rett Syndrome to see you as part of her life then get excited for her, believe that she did it even when there's not the evidence most people would expect. Someday in the future you will see how she has changed you as much as you have changed her, and that making the least dangerous assumption has brought you into a circle of trust that will change your life in significant ways -- regardless of whether anyone else in the world believes you or not.

Rett Syndrome, Long-Term Memory and Neuren Pharmaceuticals' NNZ-2566

Over the last couple months I keep getting sucked back into the question of how Rett affects long-term memory. First I saw this write-up talking about how adult women with Rett seem to have better memory for events and objects from their early childhood. Then a few weeks later I was looking up long-term memory for an unrelated project and came across mentions of our good friend BDNF. I dug in a little then, but it's coming up again now as I'm working with Becca on learning her letters, and I wanted to better understand her learning process.

BDNF

So! Here's the somewhat limited (but still long) results of my foray into the relationship between Rett Syndrome and long-term memory.

Quick refresher from my previous post on BDNF, brain-derived neurotrophic factor is a protein and gene that have various effects, mostly on the brain. I believe it is also the first identified protein that is "downstream" of MECP2 (Rett). When you compensate for a BDNF deficiency in a mouse with Rett, their heart begins to function properly, their energy and strength improve -- many of the main symptoms of Rett are lessened significantly.

Then what about BDNF and long-term memory? Long-term memory is (I believe) defined as anything that's remembered for more than around eight hours. That includes childhood memories, lessons from school last year, and what you learned yesterday in class. The process of long-term-memorization seems to be getting something into short-term memory, then transitioning it to long-term memory and strengthening its placement in long-term memory over time. BDNF does a lot for the brain and is deficient in Rett Syndrome, so that's a great starting point for research.

 The first article I found was a winner, "BDNF is essential to promote persistence of long-term memory storage". The study shows two things, 1: BDNF is necessary for long-term memory persistence as part of a process that happens at some point after the original learning experience, and 2: even when other components of the long-term persistence process are missing ("hippocampal protein synthesis" is apparently the other part of the process), BDNF alone is enough to persist the long-term memory -- "in an ERK-dependent manner".

Cue the vocab lesson :-). Gathering these terms was no small feat, the neuroscientists of the world do not like to share their language with us peons.

Protein synthesis - the creation of proteins by cells. Hippocampal protein synthesis is the creation of proteins by brain cells, and is necessary for the brain to create connections. Apparently even if you suppress protein synthesis in the brain, a sufficient supply of BDNF is enough to allow for long-term memory. BDNF pretty much rocks.

Kinase - a kinase is an enzyme that allows for energy transfer. If I understand this correctly, a kinase is essentially a pathway through which actions can occur.

ERK - extra signal-related kinase. This is a specific kinase that is "activated" or used by, among other things, BDNF and growth factors (IGF-1, anyone?). This study was focused on spine growth, but showed that BDNF most definitely leverages the ERK "path" for its purposes.

CREB - CREB is a transcription factor (a protein) that helps regulate the transcription of certain DNA pieces. In other words, when a cell uses its DNA to send a message via RNA to create certain proteins,  needs transcription factors like CREB in order to send the correct message and have the protein created correctly. CREB regulates the transcription of a number of genes including BDNF.

Thanks for sticking with me, here's a picture.
CREB != crab.

PKMζ - PKMζ is another kinase. It appears that this kinase is necessary for the maintenance of long-term memory. Without it existing long-term memories seem to break down.

Akt/mTOR - Akt and mTOR are two kinases that I see lumped together a lot in the papers I'm looking at. The Neuren study implies they are a joint pathway that is inhibited by Rett Syndrome (more on that in a minute). 

IL-6 - this is a protein that is somewhat similar to BDNF and IGF-1. It does a bunch of cool stuff. I honestly haven't dug into it much, but the Neuren study suggests that their new drug may help via the IL-6 route in addition to the IGF-1 route. The only other paper I could find mentioning Rett and IL-6 wasn't directly related (but is wicked interesting and I'm going to dig into it later for sure).

Sorry, that was rough, but hopefully it'll help if you decide to dig in to any of the linked papers. I can proudly say I understand at least 30% of the Neuren presentation now :-). Anyway, back to our research. 

BDNF can facilitate long-term memory via ERK. In fact, another study said BDNF is a requirement for ERK activation (and also that CREB is necessary for correct ERK activation). There also appears to be a time element involved. In yet another study Alonso and company found that injecting rats with BDNF blockers prevented learned fear reactions -- but only some of the time. When BDNF was blocked 15 minutes before, or 1 or 4 hours after the training then the rats didn't developer the learned reaction, but when blocked at training time or 6 hours after, it had no effect. There were a few other studies that talked about time-critical moments in the long-term memory process. If there were a way to temporarily increase BDNF it seems like it could be done at a strategic time in order to improve retention when teaching new topics.

So is there anything to be done? Not sure. The whole "BDNF is necessary and also sufficient" thing is kind of a downer. I found some articles on how dopamine (2) and PKMζ increases can enhance long-term memory, but if BDNF is a must-have then I don't see how useful that is for Becca. Maybe it would help some even if it doesn't remove the main barrier, I don't know. I did also find some articles on memory strategies, the most promising of which is to try to encourage connections between existing long-term memories when introducing a new idea ("B" is for "bus", you ride the school bus every day to school), which can essentially make it more likely the idea will be pulled along into long-term memory (though somewhat paradoxically, novelty encourages attentiveness which improves retention as well). I'm trying to offer more variety while I teach Becca, pulling in both familiar and novel concepts, to hopefully do what I can to help her with retention.

Obviously long-term memory isn't completely nonexistent since Becca recognizes people from the past, she remembers things she doesn't like (her car seat) and things she does like (Wall-E, chocolate). She seems to recognize places she's been before. But when I work with her on school topics, it feels like she has a harder time making things stick between sessions. That's what this study says, too, that LTP exists in a weakened way in individuals with Rett Syndrome.

Oh right, LTP is another vocab word. Long-term potentiation is the biological process that most likely equates to long-term memory. They strongly correlate, anyway. As I look at my old notes, I remembered there were Rett studies mentioning plasticity, so I did a quick check on the relationship between plasticity and LTP. Apparently LTP is one type of plasticity, so if your plasticity is messed up then your long-term memory is probably messed up too. Like with Rett Syndrome.

Ok, so we're basically hosed when it comes to long-term memory, we do what we can but it's a very uphill battle. Lots of studies showing poor plasticity caused by Rett Syndrome. But remember, the IGF-1-as-a-replacement-for-low-BDNF studies on mice with Rett showed significantly improved plasticity (which should also mean improved long-term memory).

In fact, that's one of the main areas of study for Neuren Pharmaceutical's research drug, NNZ-2566. NNZ-2566, they claim, is an "analogue" of IGF-1 that can be taken orally but can still cross the blood-brain barrier, which is what needs to happen if it's going to have a positive impact on brain function.

Neuren has performed studies on mice where they "knocked out" or disabled FMR1, which is the equivalent of giving someone Fragile X. Fragile X is obviously not the same thing as Rett Syndrome (they may even be on opposite ends of the spectrum), but there are both genetic disorders with neurologic impact and do have some similar characteristics. Not sure I'm reading things right, but it seems like Fragile X *might* have the same problem of too little BDNF in the brain... The relationship between Fragile X and BDNF (search results) doesn't seem as cut-and-dry to me as with Rett, but I'm having a harder time understanding those results so don't read too much into that.

As far as the Neuren study goes, the Fragile X mice showed poor long- and short-term memory in different mazes when compared to wild-type mice. When placed in a simple maze 10 minutes and 24 hours after an initial exposure, the Fragile X mice were exploring the maze anew while the wild-type mice more quickly re-settled into their environment. In a different maze with essentially tall cliffs, the wild-type mice spent significantly less time on the anxiety-inducing cliffs than did the Fragile X mice. When given NNZ-2566 the Fragile X mice performed basically the same as the wild-type mice in both mazes.

Only one of these things has a head
full of fluff.  Also, stripes are cuter
than polka-dots.

So that's potentially very promising. It says to me that NNZ-2566 as an IGF-1 alternative may be a sufficient supplement for a BDNF deficiency as far as memory is concerned. We know from the other study I linked to before that IGF-1 positively affects brain weight and plasticity of Rett mice, so maybe that's enough of a correlation to be hopeful for Rett in addition to Fragile X. 

At any rate Neuren is working on Phase II of a clinical trial for NNZ-2566 as a treatment for Rett Syndrome. They are looking for adolescent and adult subjects (if I remember correctly, they're targeting older subjects because IGF-1 is a *growth* hormone and they don't want any confounding factors from younger subjects who are still growing), though if the drug is effective they will obviously work for approval for younger cases as well. They claim that in pre-clinical models of TBI, Fragile X and Rett there was a "normalization of Akt and ERK activation profiles" (you know what that means now, sort of!). Hopefully the clinical trials will back up their previous research.

What do the rest of us do in the mean time? Be patient is all I can suggest :-). It's been a tricky balance as I've been working with Becca on "school time" because she seems to remember enough to get annoyed if I'm too repetitive or spend too many days on the same subject, but it's also clear there are holes in her understanding that I need to fill before I can go too much farther. It does help to know there's the potential for learning, and that I'm not crazy in thinking she's getting it albeit sometimes at a slower pace. Even with all of her constraints she still surprises us quite often with what she knows or remembers, we just have to believe in her and keep remembering to ask.

Becca Can!

Becca really wanted to go the pool a few weeks ago.

We're in the middle of a little "adventure" dealing with the school's perspective on Becca. I don't want to go into it in this blog post, because I don't want to jump to conclusions, but for first grade Becca was put into the "medically intensive" room. I've been all kinds of frustrated and worked up making assumptions about why the school did this and how it's going to be this huge uphill battle to get what I consider a problem to be fixed, but that's a post for another day.

The only reason I bring it up is because as part of prepping for our meetings I've been making a list of the things Becca *can* do. I was pleased by the list, and to me it makes it pretty clear Becca is "in there" and she just needs people who believe that's true in order for her to succeed. We have made so much progress even just over the summer, I'm honestly a little scared to lose it if I can't get the school on board.

Here's what Becca can do:

- reach out in front of her when something she wants is in front of her (i.e. toy boat in the pool, toy dog on the floor, candy crush on the tablet, communication switch)

- make eye contact to confirm a question ("yes", i.e. "is yellow your favorite color" "do you want to go to the pool")

- not make eye contact to say "no" to a question (i.e. "do you want to go outside", "do you want to stay home from school today")

- not make eye contact when she knows the answer is "yes", then laughing when we "catch" her (i.e. "did you poop", "did you go swimming at school today", "do you love your brother")

- reach out and hit a large communication switch she knows is for communication without prompting

- look directly at something she wants (i.e. crackers, tv, a different pillow, etc.)

- look back and forth between something she wants and the person who can get it for her (i.e. tv to grandma)

- reach out quickly and grab something she is interested/bothered by (i.e. nasal canula breathing tube, syringe full of formula, baby brother's face)

Becca's sister is such a good helper

- laugh when she is able to physically touch or hit something in a way that causes an upset or surprised reaction (i.e. messing up Paula when playing Candy Crush, knocking over the syringe full or formula while feeding, hitting Christopher in the face to make him cry)

- make verbal noises when something is mentioned she is excited about (i.e. "we're still planning to go to the pool tomorrow" resulted in a "gie-ood" noise and excited laugh, "tomorrow is Christmas!" was similar)

- have opinions about decisions (i.e. grandma really wanted to get her to watch Brave, she kept picking everything but Brave)

- have a preference for who to communicate with (didn't want to tell Paula she wanted to go to school, she wanted to tell me)

- not say yes or no when she's not in the mood (i.e. shopping at target she wouldn't pick, wouldn't "engage" to be able to say either yes or no)

- pick the option that we're pretty sure isn't her favorite, just because her sister wants the other one (i.e. what movie to watch)

- eye gaze at a communication system (on a tablet) with 6 items, with person vocalizing the items "selected", then confirming she wanted where we ended up on the communication system

- look directly at someone when she knows they can help her communicate a desire/interest (i.e. someone she knows can get her communication board)

- look directly to something that is conceptually related to another point or idea (i.e. I helped her cheer "Go BYU!" and she then looked directly at my BYU t-shirt, "do you know what time it is" and she looked directly at my watch)

I also realized lately that a lot of the time Becca spends at home isn't very challenging or even stimulating for her, it's watching shows and playing with toys that she's mastered a long time ago. I want to start working with her at least some at home now, so I started that today. Here's what happened:

9/1/13

We read Memoirs of a Goldfish (which is a really cute book, by the way). I asked Becca who the story was about, who was in it from the start, and she picked Cha-Cha (the story is about the goldfish, not Cha-Cha. I probably should have asked her something better, like who was telling the story). So we talked about it and how the goldfish is the one in the whole story, so that's who I would have picked. 

Then I asked her which character she liked better, Mr. Bubbles or Mervin. She picked Mervin, so I talked about what was silly about Mervin, then we talked about what was silly about Mr. Bubbles. Then her sister picked between the guppies and Cha-Cha, she picked the guppies, then we talked about why she liked the guppies better. 

After that we tried to identify which fish appeared in the story in which order. Becca and her sister took turns picking between two options, and they both picked correctly every time. Then I asked Becca which fish the goldfish liked better, Gracie or Cha-Cha. Becca picked Gracie, which makes sense since Gracie is also a goldfish and the goldfish likes swimming around the pool with her. Then Becca and her sister took turns putting the fish in order again, and there were no mistakes that time either.

I wasn't sure what to expect from this exercise, but by keeping the tone very conversational rather than making it sound like a test we did a lot better than times I've tried before. I think we're in for some more surprises as we keep trying to help her get out of her shell :-).